In order for an ophthalmic drug to be therapeutically effective, it is generally necessary for the drug to penetrate the cornea, where it may be taken up in the aqueous humor and other tissues in the inner eye. Drugs or drug products which act on the exterior surface of the cornea for treating dryness or irritation. Thus, the treatment of physiological conditions within the eye requires the movement of topically applied ophthalmic drugs through the cornea.
To pass through the cornea, a drug must penetrate three layers of tissue, namely, the epithelium, stroma and endothelium. Lipid soluble compounds more easily penetrate such membrane barriers that are rich in lipids, while water soluble compounds more easily penetrate water rich membrane barriers. The epithelial and endothelial cell membranes are relatively lipid rich, while the stroma has a relatively high water content. Since topically applied drugs must penetrate these differently structured barriers, it would appear that an ideal drug compound should be both lipid and water soluble.
The stroma and endothelium together are approximately 360 microns thick and these layers allow penetration by aqueous solutions through a process of inter-cellular diffusion. There is no particular need for enhancing the aqueous diffusion rate through the stroma or endothelium, since the epithelium is the only operative barrier to aqueous penetration of the cornea. Therefore, enhanced penetration of topically applied aqueous drugs through the corneal epithelium would proportionately increase the total drug dosage absorbed into the eye as is obviously desirable.
Prior to the present invention, there have been attempts to enhance the penetration of drugs through the corneal epithelium to an optimal point at which the stroma alone controls drug transport through the cornea. These attempts have included use of chemical agents to enhance drug penetration of the epithelium. It has been reported that benzalkonium chloride (BAC), bile salts, dimethyl sulfoxide (DMSO), ethylenediamine tetraacetate (EDTA) and 1-dodecylazayl-cycloheptan-2-one (AZONE&lt;&lt;)enhance the corneal penetration of certain drugs. The following publications may be referred to for further background concerning the use of such agents to enhance corneal penetration: Acta Ophthalmological, Vol. 53, p. 365 (1975); J. Phar. Pharmacol. Vol. 39, p. 124 (1987); Chem. Abstracts, Vol. 106, 125934t, p. 402 (1987); Journal of Pharmaceutical Sciences, Vol. 77, No. 1 (January, 1988); and Investigative Ophthalmology and Visual Science, Vol. 29, No. 2 (February, 1988). Notwithstanding such prior attempts, there continues to be a need for a means of safely and effectively enhancing the penetration of the cornea by ophthalmic drugs in aqueous solution.
A first object of the present invention therefore, is to provide an improved rate of epithelium penetration by topical ophthalmic drugs in aqueous solution. A second object is that this improved penetration rate be achieved in a completely safe manner, without ocular irritation or other undesirable side effects. A third object is that methods of the present invention be simple and readily accomplished without the need of clinical oversight.